Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds

ABSTRACT

NEW ALKYL SULFONIC ACID ESTERS OF 1,3,1-OXAZAPHOSHPACYCLIC COMPOUNDS OF FORMULA 1   R-ALK-N(-R1)-P(=X)&lt;(-N(-R2)-CH2-(-CH2-C(-Z)2-CH2-)M-CH2-   O-)   THESE NEW COMPOUNDS PRODUCE A HIGH IMMUNSUPPRESSING ACTIVITY IN HUMANS.

United States Patent US. Cl. 260456 A 4 Claims ABSTRACT OF THEDISCLOSURE New alkyl sulfonic acid esters of 1,3,2-oxazaphosphacycliccompounds of formula I These new compounds produce a highimmunsuppressing activity in humans.

The present invention is related to alkyl sulfonic acid esters of 1,3,2oxazaphospha-cyclic compounds which produce a high immunsuppressingactivity. The invention is further related to process for the productionthereof and to pharmaceutical preparations containing the same.

The new compounds according to the present invention correspond to theformula I wherein R is a halogen atom, preferably a chlorine atom, or alower alkyl sulfonic acid group having a straight or branched loweralkyl chain with 1 to 6 carbon atoms, R and R are hydrogen or a loweralkyl group with 1 to 4 carbon atoms which alkyl group may besubstituted with a halogen atom, preferably a chlorine atom, or with alower alkyl sulfonic ester group having a straight or branched loweralkyl chain with 1 to 6 carbon atoms, R and R being identical ordifierent from each other and there being present in the molecule offormula I at least one such lower alkyl sulfonic acid ester group, andalk represents a straight or branched alkylene group with 2 or 3 carbonatoms in the chain and, if branched, with a total of 3 or 4 carbonatoms, X represents oxygen or sulphur, Z represents a hydrogen atom or alower alkyl group having from 1 to 4 carbon atoms and m is 2 or 3.

Because of their favourable compatibility those compounds of formula Iare preferred, wherein X is oxygen. Because of their highimmunsuppressing activity, those compounds are particularly preferredwhich have the formula II wherein R, R R and alk have the same meaningas in formula I. Among these compounds of formula II the compounds offormula III CHzCHzOl N-CH: R7SO508lk-NH-P==0 OCH3 III are particularlypreferred, wherein R is an unsubstituted lower alkyl group having from 1to 6 carbon atoms in a straight or branched chain and alk is the groupCHCHz-, -(i7HCHa or -CHa(l'JH-,

CH3 CgHs in particular the group CH CH Among this group of compoundsthose compounds show a particularly high immunsuppressing activity andtherefore are most preferred wherein alk is CH CH and R is the methyl orethyl group or alk is -CHCH1 and R is the methyl group.

It is surprising that the compounds of formula I show a strongimmunsuppression which activity has not been known up to now with alkylsulfonic acid esters. The compounds of the following Examples 1 and 3-6in particular produce a substantial or even complete suppression ofantibody formation until the 7th day after the administration of theantigen. The immunactivity in connection with the Brucella immunisationof rats is used to demonstrate this activity.

The new compounds of formula I are produced by using methods known assuch. The process for the production of the compounds according to thepresent invention comprises (A) Subjecting a compound of formula IVwherein R has the same meaning as R, in formula IV and Z and m have thesame meaning as in formula I, or

(B) subjecting a compound of the general formula VI Ra-alk-NH a VIwherein R and R have the same meaning as in formula IV and alk has thesame meaning as in formula I, to reaction with a compound of formula VIIl a N 0 VII wherein X has the same meaning as in formula IV, R has thesame meaning as in formula V and X, Z and m have the same meaning as informula I, or

(C) subjecting a compound of formula VIII wherein R has the same meaningas in formula V and X, Z, alk and m have the same meaning as in formulaI, to reaction with a compound of formula IX wherein R; has the samemeaning as in formula IV, and converting the hydroxy groups in theresulting compounds of formula X wherein one or several of the R R and Rgroups represent or carry a hydroxy group, into a halogen atom or thegroup --OSO R R being a straight or branched lower alkyl group havingfrom 1 to 6 carbon atoms, by subjecting said hydroxy compounds toreaction with a halogenating agent or a sulfonic acid halogenide Rhaving the same meaning as above and Hal being a halogen atom,preferably a chlorine atom and, if desired, exchanging one or severalhalogen atoms in the resulting compounds of formula X, wherein none ofthe R R and R groups represent or carry a hydroxy group and one orseveral of the R R and R groups represent or carry a halogen atom,against the groupment -OSO R by subjecting such a compound of formula Xto reaction with a compound of formula XI MeOSO R XI wherein R, has theabove given meaning and Me is a metal 'of the first or second main orsub-group of the periodic system of elements, and preferably is silver.

The reactions are preferably carried out in the presence of an inertsolvent such as acetonitrile or a lower halogenated hydrocarbon such aschloroform or methylene chloride, or in an ether such as diethylether ordioxane, or in an aromatic hydrocarbon such as benzene or toluene. Thereaction is carried out at an elevated temperature ranging from roomtemperature to the boiling point of the reaction mixture.

The reactions are preferably carried out in the presence of an acidbinding agent. The acid binding agent should be present in an amountranging from 1 to 2 mole equivalents. There are numerous known alkalinecompounds which may be used as acid binding agents such as alkali metaland alkaline earth metal carbonates and bicarbonates and particularlytertiary mines such as triethylmine and pyridine.

Halogenating agents for exchanging aliphatically bound hydroxy groupsagainst halogen atoms are also known. Useful for this purpose are forinstance the phosphorous halides such as phosphorous trichloride ortribromide, phosphorous pentachloride, phosphorous oxychloride oroxybromide, the sulfurous and sulfonic acid halides such assulfurylchloride and thionylchloride, or phosgene. Thionylchloride ismost preferably used in view of the ease to handle it.

Usual carrier products for pharmaceutical preparations, which maycontain a compound according to formula I as active agent, arepharmacologically inert products as they are known for the production oftablets, drages, suppositories and injection solutions.

The following examples further illustrate the present invention withouthowever limiting the same thereto. The compounds according to thepresent invention are characterized by their infrared spectra and showcharacteristic P=O bands at 1188 to 1275 emf- C-SO -C- bands at 1330 to1376, 1165 to 1175, 905

to 975 and 787 to 805 cm.

P0C- bands at about 1050 and 975 cmr and NH- bands at 3200 to 3300 cmrEXAMPLE 1 2- (2-Methylsulfonoxyethylamino -3- (2-chloroethyl)tetrahydro-ZH-l 3 ,2-oxazapho sphorine-2-oxide A solution of 113.2 g. ofchloro-3-(2-chloroethyl)-tetrahydro-2H-l,3,2-oxazaphosphorine-2-oxide in360 cc. of anhydrous dioxane are added dropwise at l5-18 C. to asolution of 31.6 g. of ethanolamine and 57 g. of triethylamine in 300cc. of anhydrous dioxane. Stirring is continued for one hour at 3035 C.Thereafter, the precipitated triethylamine hydrochloride is filtered olfwith suction and the filtrate is evaporated in a Water jet vacuum. Theresidue is washed 3 to 4 times with each cc. of ether. After drying in ahigh vacuum, the resulting 2-(2 hydroxyethylamino) 3(2-chloroethyl)-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtainedas a faintly yellow oil.

Yield: 121.3 g. (97% of the theoretical).

A solution of 121.3 g. (0.5 mole) of the above compound and 50.6 g. (0.5mole) of triethylamine in 320 cc. of dioxane is prepared. This solutionis added to a solution of 57.3 g. (0.5 mole) of methane sulfonic acidchloride in 340 cc. of dioxane dropwise within 30 minutes at 26-28 C.Thereafter, 150 cc. of ether are added and stirring at 10 C. iscontinued for another 30 minutes. The precipitated triethylaminehydrochloride is filtered off with suction and the filtrate isevaporated at 30-35 C. in a water jet vacuum. Ether is added to the oilyresidue which crystallizes while standing in an ice box after seeding.The product is purified by dissolving it in etha nol and adding ether tothe ethanolic solution and allowing to stand in the ice box. The productis obtained in nice colorous crystals upon extraction in a soxhlet apparatus with a mixture of methylene chloride and ether.

Yield: 111 g. (69% of the theoretical).

EXAMPLE 2 2-(3-Methylsulfonoxypropylamino)-3-(2-chloroethyl)-tetrahydro-ZH-l,3,2-oxazaphosphorine-Z-oxide A solution of 37.4 g. of2-chloro-3-(2-chloroethyl)- tetrahydro-2H-l,3,2 oxazaphosphorine-Z-oxidein 140 cc. of anhydrous dioxane is added dropwise to a solution of 12.95g. of propanolamine-l,3 and 17.3 g. of triethylamine in 140 cc. ofanhydrous dioxane dropwise with stirring within 50 minutes at atemperature ranging from 15 18 C. The precipitated triethylaminehydrochloride is filtered off with suction and the filtrate isevaporated in a water jet vacuum. The residue is washed several timeswith ether. Upon drying in a high vacuum, the resulting 2-(3hydroxypropylamino) 3(2-chloroethyl)-tetrahydro-2H-l,3,2-0xazaphosphorine-Z-oxide is obtainedas a highly viscous clear oil.

Yield: 38.6 g. (86% of the theoretical).

A solution of 38.6 g. of the above compound and 15.5 g. of triethylaminein cc. of anhydrous dioxane is added to a solution of 17.2 g. of methanesulfonylchloride in 120 cc. of anhydrous dioxane dropwise with stirringWithin 30 minutes at a temperature ranging from 28-30 C. The separatedtriethylamine hydrochloride is filtered ofi with suction and thefiltrate is evaporated in a water jet vacuum. The oily residue isdissolved in water and purified by means of the ion exchanger Duolit (A102). Anhydrous ether is added to the colorless oil and the mixture iscooled in an ice-bath and scratched from time to time. Thus, the productcrystallizes. The crystals are recrystallized from ethyl acetate.

Yield: 13.9 g.

EXAMPLE 3 2-( 2-Ethy1sulfonoxyethylamino) -3-(2-chloroethyl)-2H-tetrahydro-l ,3,2-oxazaphosphorine-2-oxide A solution of 24.3 g. of2-(2-hydroxyethylamino)-3- (2-chloroethyl)-2H-tetrahydro 1,3,2oxazaphosphorine- 2-oxide (prepared as described in Example 1) and 10.1g. of triethylamine in 60 cc. of anhydrous dioxane is added to asolution of 12.9 g. of ethane sulfonylchloride in 70 cc. of anhydrousdioxane dropwise with stirring within 20 minutes at a temperatureranging from 28-30 C. The reaction mixture is allowed to stand for 1hour. Thereafter, the precipitated triethylamine hydrochloride isfiltered off with suction. The solvent is evaporated in a vacuum and theresulting oily residue is purified by first extracting in a perforatorwith ether and then with a 2:1 mixture of methylene chloride and ether.The first ethereal extract is discarded. The solvents are evaporatedfrom the methylene chloride/ether extracts and the resulting productcrystallizes upon standing in the ice-box. The compound isrecrystallized from methanol/ether.

Yield: g.

EXAMPLE 4 2- (2-Propylsulfonoxyethylamino) -3- (2-chloroethyl -2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide A solution of 24.3 g. of2-(2-hydroxyethylamino) -3-(2- chloroethyl) 2Htetrahydro-l,3,2-oxazaphosphorine-2 oxide (prepared as described inExample 1) and 10.1 g. of triethylamine in 170 cc. of anhydrous dioxaneis added dropwise to a solution of 14.3 g. of n-propylsulfonylchloridein 70 cc. of anhydrous dioxane dropwise with stirring and cooling withinminutes at a temperature ranging from 28-30" C. Stirring is continuedfor a short period of time at 30 C. Thereafter, 60 cc. of anhydrousether are added, the mixture is cooled to 10 C. and stirring iscontinued for another half hour. The separated triethylaminehydrochloride is filtered oif with suction and the filtrate is filteredover activated charcoal and evaporated in a water jet vacuum. The oilyresidue is extracted in a perforator with a 1:1 mixture of ether andmethylene chloride. The extract is allowed to stand in the ice-box andis scratched several times thus causing the desired product tocrystallize. The crystals are recrystallized from the same solventmixture.

Yield: 14 g.

EXAMPLE 5 2-(2-Isopropylsulfonoxyethylamino)-3-(2-chloroethyl)-ZH-tetrahydro-1,3,2,-oxazaphosphoriue-Z-oxide A mixture of 24.3 g. of2-(2-hydroxyethylamino)-3-(2- chloroethyl) 2Htetrahydro-1,3,2-oxazaphosphorine-2- oxide (prepared as described inExample 1) and 10.5 g. of triethylamine in 75 cc. of dioxane are addedto a solution of 14.3 g. of isopropane sulfonylchloride in 70 cc. ofdioxane dropwise within minutes at a temperature ranging from 28-30" C.The separated triethylamine hydrochloride is filtered off with suction.The solvent is evaporated in a water jet vacuum and the oily residue iswashed with ether in a perforator for 2 hours. Thereafter, it isextracted twice with a mixture of methylene chloride and ether. Theextracts are filtered over activated charcoal and evaporated. Thus, aclear yellowish and highly viscous oil is obtained which is purifiedchromatographically over a column of silica gel in methylene chloride.

Yield: 16.4 g. (47% of the theoretical). n 0: 1.4927.

EXAMPLE 6 2- (2-n-Pentylsulfonoxyethyl amino -3- (2-chloro ethyl)2H-tetrahydro-1,3,2-oxazaphosphorine-Z-oxide A solution of 24.3 g. of2-(2-hydroxyethylamino)-3- (2chloroethyl)-2H-tetrahydro-1,3,2-oxazaphosphorine- 2-oxide (prepared asdescribed in Example 1) and 10.5 g. of triethylamine in cc. of dioxaneis added to a solution of 17.1 g. of n-pentylsulfonylchloride in 75 cc.of dioxane dropwise with thorough stirring and cooling such that thetemperature does not rise above 35 C. Stirring is continued for anotherhalf an hour. The precipitated triethylamine hydrochloride is filteredoff with suction and the filtrate is evaporated in a water jet vacuum.The resulting oil is dissolved in chloroform and washed with dilutehydrochloric acid, a sodium bicarbonate solution and water. The thustreated solution is again evaporated. The residue is extracted withether in a perforator. The ethereal extract is allowed to stand in anice-box whereupon the desired final product crystallizes. It isrecrystallized from ether.

Yield: 10.5 g. (27.8% of the theoretical).

EXAMPLE 7 The following recipe is used for the production of 100,000drages containing each 50 mg. of the active compound according to thepresent invention:

The crystalline active compound is passed together with 3 kg. of cornstarch through a sieve having a mesh size of 1 mm. The products arethoroughly mixed and a paste is formed with a 10% solution of theolyvinylpyrrolidon in isopropanol. The moist product is granulated bypassing it through a sieve having a mesh size of 3 mm. It is then driedand ground to a particle size of 1 mm. Finally, the remaining auxiliaryproducts of the above recipe are sieved and thoroughly admixed and100,000 drages are pressed each weighing mg., having a diameter of 7 mm.and a camber diameter of 6 mm. The resulting kernels are coated inmanner known per se by first applying a lager resistant to the gastricjuices giving each kernel a weight of mg., then applying a cover until akernel weight of 205 mg., smoothing the surfaces of the kernels until akernel weight of 215 mg. and thereafter applying color layers up to akernel weight of 240 mg. Finally, the coated kernels are rendered glossyby applying a layer of hard wax.

EXAMPLE 8 A dry mix of active compound and sodium chloride is filledinto glass to be for the production of injection solution. In the laststep of purification by recrystallization of the active compoundaccording to Example 1, the solution thereof is passed through a filterholding back germs. The further processing is effected under asepticconditions. The crystallized compound is separated by centrifugation anddried and held in an atmosphere of ethylene oxide. A sample is taken andchecked for purity and sterility. After clearance of further processingis obtained, the compound is mixed with sterile sodium chloride pa. in aweight proportion of 100 to 45 under aseptic conditions,

thus producing a finely divided homogenous mix. Another sample is takenand tested for its content in active compound, for sterility and freedomof pyrogenous compounds. After clearance of further processing, 145 mg.of the mix are filled into flasks of 10 ml. each under asepticconditions and in an atmosphere of nitrogen. The flasks are closed withaseptic stoppers of butyl caoutchouc. The final check is made inaccordance with the recommendations of the section Testing for GoodQuality and Sterility of the German Federal Health Administration. Inorder to produce injection solutions, cc. of water purified forinjection solutions are added to the content of a flask which isdissolved therein.

The compounds according to the present invention are useful in thetreatment of autoimmune diseases (autoaggressive diseases), such asautoimmunehaemolytic anemia, lupus erythematodes and polyarteritisnodosa. The compounds are preferably applied in a daily dose rangingfrom 2 to 4 mg./ kg. A particularly useful and therefore most preferredcompound is that of Example 1.

What we claim is:

1. An alkyl sulfonic acid ester of 1,3,2-oxazaphosphacyclic compounds ofthe formula III wherein R7 is a straight or branched lower alkyl grouphaving from 1 to 6 carbon atoms and alk represents a straight orbranched alkylene group having 2 or 3 carbon atoms in the chain and, ifbranched, having a total number of 3 or 4 carbon atoms.

2. A compound according to claim 1 wherein alk is 3. A compoundaccording to claim 1 wherein alk is CH CH and R is methyl or ethyl, oralk is -(i}HCH2- and R is methyl.

4. 2-(2-Methylsulfonyloxyethylamino) 3 (2-chloroethyl) -te trahydro2H-l, 3 ,2-oxazaphosphorine-Z-oxide.

References Cited FOREIGN PATENTS 1,197,882 8/1965 Germany 260-456 R LEONZITVER, Primary Examiner N. MORGANSTERN, Assistant Examiner US. Cl. X.R.260-936; 424209 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIONPatent No. 3,828,090 Dated August 6 197"- Inventor(s) Herbert Arnold etal.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Golf 3, Line 62, "mines" should read amines Col. 6, Line 5, "n O" shouldread Col. 7, -Claim 1, the structural formula should read as followsz'CH CH Cl N-- cni 7 I 'R- -sO -O alk-NH-P o /cH Signed and sealed this3rd day of December"1974.

(SEAL) Attest:

McCQY GIBSON JR. C.-- MARSHALL DANN Attestlng Officer Commissioner ofPatents Po H 9) USCOMM-DC 00370-909 11.5. Gavin "HINT 'IINTHIG OFFICE 20-366-3

